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Published on: May 24, 2014
Integrated omics analysis identifies mechanical irritation as a driver of OSCC progression via the HIF-1α/ASC/NLRP3
Hsin-Pai Li1, Jui-Lung Hung2, Sheng-Ning Yuan2
1Molecular Medicine Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department of Microbiology and Immunology, Chang Gung University, Taoyuan City 33302, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan City 33305, Taiwan.
Background:
Mechanical irritation can lead to traumatic ulcers in the oral cavity and is a potential risk factor for oral cavity squamous cell carcinoma (OSCC). Habitual betel nut chewing reportedly has the potential to induce mechanical irritation and OSCC, but the details of the underlying mechanism(s) remain unknown.
Materials And Methods:
By integrating transcriptomic and proteomic data from 83 OSCC patients with our in vitro mechanical cell abrasion (MCA) model, we explored mechanical irritation-driven OSCC progression, including inflammasome activation, migration, invasion, and colony formation, and revealed underlying mechanisms via potassium efflux, ChIP-qPCR, co-IP, and immunofluorescence.
Results:
We observed that the combination of betel nut alkaloid, arecoline, and MCA demonstrate a synergistic effect on inflammasome activation in OSCC cells. MCA could cause membrane injury, resulting in the efflux of lactate dehydrogenase and potassium ions; this could activate the NLRP3 inflammasome complex to facilitate the production of IL-1β and the nuclear translocation of the HIF-1α/NLRP3/ASC complex, which activated the HIF-1α oncogenic downstream target, ADAM8. Higher ADAM8 mRNA levels in tumors were correlated with poor prognosis in OSCC. Upon MCA treatment, the colocalization of HIF-1α, NLRP3, and ASC was enriched in the nucleus, leading to elevated inflammasome and tumorigenic responses, respectively, in OSCC cells.
Conclusions:
Our MCA model simulating betel nut chewing induces membrane damage, activates the HIF-1α/NLRP3/ASC pathway, and enhances crosstalk between inflammation and HIF-1α signaling. Omics and clinical data reveal that ADAM8, a HIF-1α downstream target, may serve as a poor prognostic marker in OSCC.
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